Process for producing 4 6-dihalopregna-4 6-diene

ABSTRACT

A PROCESS FOR PRODUCING 4,6-DICHLORO-16-ALKYLIDENE PREGNA-4,6-DIENE-3,20-DIONES USEFUL AS PROGESTATIONAL AGENTS FROM 3-LOWER ALKANOYLOXY-17-HYDROXY-16-ALKYLIDENE-PREGN-5-EN-20-ONES, AND INTERMEDIATES THEREIN.

United States Patent- Oflice 3,655,653 PROCESS FOR PRODUCING 4,6-DIHALOPREGNA- 4,6-DIENE Richard Wightman Kierstead and Perry Rosen, North Caldwell, N.J., assignors to Holfmann-La Roche Inc., Nutley, NJ. N Drawing. Filed Dec. 11, 1969, Ser. No. 884,323 Int. Cl. C07c 173/00 US. Cl. 260-23955 25 Claims ABSTRACT OF THE DISCLOSURE A process for producing 4,6 dichloro 16 alkylidene pregna 4,6 diene 3,20 diones useful as progestational agents from 3-lower alkanoyloxy-l7-hydroxy-16-alkylidene-pregn--en-20-ones, and intermediates therein.

SUMMARY OF THE INVENTION In accordance with this invention, a process is provided for synthesizing progestational agents of the formula:

"0 Ra a wherein R and R are chlorine or bromine; R is lower alkylidene and R is hydrogen or lower alkanoyl;

from a compound of the formula:

wherein R is as above and R is a lower alkanoyl;

3,655,653 Patented Apr. 11, 1972 via an intermediate wherein R and R are as above; R is chlorine or bromine, and

n is an integer from 0 to 5.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term halogen comprehends all four halogens, such as chlorine, fluorine, bromine and iodine, with chlorine being the preferred halogen. The term lower alkyl, as used herein, comprehends obth straight and branched chain saturated hydrocarbon moieties having from one to six carbon atoms, such as methyl, ethyl, t-butyl, n-pentyl or the like. The term halo lower alky includes mono and di-substituted halo-lower alkyl moieties such as chloro-methyl, 2-chloro-ethyl, 3-bromopropyl, 1,2-dich1oro-ethyl with chloro-methyl being preferred. The preferred halo-lower alkyl moieties are those halo-lower alkyl moieties wherein the halo group is attached to the same carbon atom which is attached to the steroid nucleus. The term lower alkylidene indicates a straight or branched chain hydrocarbon moiety having from one to six carbon atoms, the terminal carbon atom of which has two free valence bonds such as methylene, ethylidene, isopropylidene and the like, with methylene being preferred. The term lower alkanoyl" comprehends residues of lower alkane carboxylic acids such as acetyl, butyryl, caproyl or the like. containing from one to six carbon atoms.

The compounds of Formula I above are characterized by their high degree of progestational activity. Thus, the compounds of Formula I above can be administered enterally for example, orally or parenterally, with dosage adjusted to individual requirements, in the form of conventional pharmaceutical preparations. For example, the compounds of Formula I can be administered in conventional pharmaceutical solid or liquid forms, such as tablets, pills, capsules, solutions, suspensions, emulsions or the like. These pharmaceutical preparations can contain conventional pharmaceutical carriers and excipients, such as water, talc, corn starch, polyalkylene glycols, emulsifying agents, buffering agents, agents for the adjustment of osmotic pressure, Vaseline, and the like. Though it is preferred to administer the endocrinologically useful compounds of this invention enterally, the compounds of Formula I above can also be administered topically. For this purpose, i.e., topical administration, these compounds can be administered in conventional topical administration forms, such as ointments or creams, in combination with conventional topical carriers such as petrolatum, stearic acid or the like. Also compositions containing the active ingredient of this invention can be subjected to conventional pharmaceutical processes such as sterilization or the like. Also, the pharmaceutical compositions of this invention can contain other active ingredients, Moreover, the endocrinologically active compounds can be administered as feed additives, and for this purpose can be admixed with conventional animal feeds or conventional animal premixes. Though as indicated dosages of the endocrinologically useful compounds of this invention should be adjusted to individual needs, the compound of Formula I above can be administered internally in daily dosage regimens of from about 0.005 mg./kg. to about 0.15 ing/kg. per day. The dosages can be administered in unit or divided dosage forms.

The usefulness of the compounds of this invention as progestational agents is indicated in animals, for example, the compound of this invention, when administered to estrogen primed immature female rabbits for five days shows the presence of progestational activity by a secretory type endometrial response observed on histological sections prepared from the rabbits uteri and examined microscopically. A maximal response is demonstrated by progesterone at 200 meg/kg. for five days. Whereas the compound of Formula I such as 4,6-dichloro-17-acetoxy- 16-methylenepregna-4,6-diene-3,20-dione which when administered to rabbits showed progestational activity at 10 mcg./kg./day s.c.

In accordance with the process of this invention, the compound of the Formula III above is prepared from the compound of the Formula II above via the following reaction scheme:

wherein R R R R R, and n are as above.

The compound of Formula IV above is prepared from the compound of Formula II above, as in step (a), by treating the compound of the Formula II above with a halogen which can be bromine or chlorine. In carrying out this reaction, at least 2 moles of either chlorine or bromine per mole of the compound of Formula II is reacted with the compound of the Formula II. If desired, a molar excess of chlorine or bromine can be utilized, i.e., up to 7 moles of chlorine or bromine per mole of the compound of Formula II. Generally, it is preferred to utilize from 2 to 4 moles of chlorine per mole of the compound of Formula II in this reaction. The procedure of step (a) is carried out by dissolving the halogen in a solvent. Any conventional hydrocarbons such as benzene,

toluene, etc., and halogenated hydrocarbon solvents such as methylene chloride and carbon tetrachloride can be utilized in this reaction. The preferred halogenated hydrocarbon solvent is carbon tetrachloride. The reaction of step (a) is carried out in the presence of nitrogencontaining heterocyclic base or tri-lower alkyl amine can be utilized in this reaction. Among these conventional amine bases are included pyridine, picoline, collidine, triethylamine etc. The preferred base is pyridine. Generally, this reaction can be carried out at temperatures of from about 50 C. to +50 C. It is generally preferred in carrying out this reaction to employ temperatures of from 10 C. to +10 C.

The compound of the Formula IV above is converted to the compound of the Formula V above by treating the compound of the Formula IV with a basic hydrolyzing agent. Any conventional inorganic basic hydrolyzing agent can be utilized for carrying out the reaction of step (b). Generally, it is preferred to carry out this reaction in the presence of a weak inorganic base such as an alkali metal carbonate or alkali metal bicarbonate. Generally, the potassium or sodium carbonates or bicarbonates are preferred. This reaction can be carried out in any conventional water soluble inert organic solvent. Among the conventional water soluble inert organic solvents, tetrahydrofuran and alcohols such as methanol are preferred. In carrying out this hydrolysis reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. However,

can (ca it CHR (Cl-l H if desired, higher or lower temperatures can be utilized. Generally, it is preferred to carry out this reaction at the reflux temperature.

The compound of the Formula V is converted to the compound of the Formula VI, via reaction step (c) by treating the compound of the Formula V with an oxidizing agent. In carrying out the oxidation procedure of step (c) chromium trioxide in the presence of a lower alkanoic acid such as acetic acid or a mineral acid is utilized as the oxidizing agent. The preferred oxidizing agent in this reaction is the Jones reagent (chromium trioxide in sulfuric acid and water). However, any other conventional mineral acid or lower alkanoic acids can be utilized in this reaction. Generally, this reaction is carried out at a temperature of from about 10 C. to 35 C. Generally, temperatures of from 10 C. to 10 C. are preferred.

The conversion of compounds of the Formula VI to compounds of the Formula VII above is carried out by treating the compounds of the Formula VI above, via reaction step (d), with a dehydrohalogenating agent under basic conditions. Thus, the dehydrohalogenation of step (d) can be carried out under basic conditions, i.e., in the presence of a proton acceptor such as, for example, nitrogen-containing heterocyclic bases, e.g., pyridine, picoline, or the like; or tri-lower alkyl amines, e.g., triethylamine; alkali metal salts of organic acids such as sodium acetate, potassium acetate, etc., and alkali metal inorganic bases, such as alkali metal hydroxides, e.g., sodium hydroxide or alkali bicarbonates, e.g., sodium bicarbonate. When conducted under basic conditions, a suitable solvent which may be employed for the conversion is the base itself.'However, any conventional inert organic solvents such as alcohols, for example, ethanol, methanol, etc.; ethers, for example, ethyl ether or dioxane; chlorinated hydrocarbons such as chloroform or carbon tetrachloride, may also be employed. Generally, this reaction is carried out at temperatures of from about C. to 100 C. Generally, it is preferred to carry out this reaction at a temperature of from 50 C. to the reflux temperature of the reaction medium.

The compound of Formula VII is converted to the compound of Formula VIII via reaction step (e) by treating the compound of the Formula VII with a lower alkyl enolating agent. Any conventional lower alkyl enolating agent such as triethylorthoformate can be utilized in carrying out this reaction. Generally, this reaction is carried out in an acid catalyst. Any conventional acid catalyst can be utilized in carrying out this reaction. Among the preferred acid catalysts are included sulfuric acid, toluene sulfonic acid, alcoholic hydrogen chloride, sulfosalicylic acid. Generally, this reaction is carried out in the presence of an inert organic solvent. Among the conventional inert organic solvents are included the alcoholic and ether solvets such as those hereinbefore mentioned. The preferred solvents are the ether solvents such as diethylether, and dioxane. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. However, if desired, higher or lower temperatures can be utilized. Generally, it is preferred to carry out this reaction at the reflux temperature of the reaction medium.

The compound of Formula VIII above is converted to the compound of Formula IX above by treating the compound of Formula VIII with an oxidizing agent. Among these conventional oxidizing agents which can be utilized are included, manganese dioxide, 2,3-dichloro-4,5-dicyanobenzoquinone, tertiary butyl chromate and chloranil. When manganese dioxide is utilized as an oxidizing agent in this reaction, the reaction is carried out in an organic acid solvent such as glacial acetic acid. However, with other oxidizing agents, any conventional organic solvent can be utilized in carrying out this reaction. Among the preferred solvents are the ketone or ether solvents, such as acetone or dioxane. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and at atmospheric pressure. However, if desired, higher or lower temperatures can be utilized.

In accordance with a preferred embodiment of this invention, dichlorodicyanobenzoquinone (DDQ) is utilized as the oxidizing agent in the reaction of step (f). While the compound of Formula IX can be produced by reacting one mole of the compound of Formula VIII above with one mole of DDQ, it has been found that when at least 2 moles of DDQ per mole of the compound of Formula VIII are utilized, the compound of Formula IX is prepared in higher yields and by utilizing shorter reaction times. Generally, it is preferred to utilize from 2 to 5 moles of DDQ per mole of the compound of Formula VIII above. However, if desired, greater than 5 moles of DDQ per mole of the compound of Formula VIII can be utilized. However, since no additional benefit arises from utilizing such large excesses of DDQ, it is seldom desirable to utilize over 5 moles of DDQ per mole of the compound of Formula VIII.

The compound of Formula IX can be converted to the compound of Formula X via reaction step (g) by treating the compound of Formula X with a halogen selected from the group consisting of chlorine or bromine. This step may be facilitated by the addition of a catalytic amount of an anhydrous mineral or organic acid. Preferred, among these acids, are the hydrohalic acids, e.g., hydrogen chloride. This reaction is generally carried out in an inert organic reaction medium for example, ethers such as the lower alkyl esters which include, ethyl ether and dioxane; halogenated hydrocarbons which include chloroform, carbon tetrachloride, ethylene chloride or methylene chloride or the like, etc. The preferred solvents for utilization in this reaction are the halogenated hydrocarbons. The halogen can be introduced by conventional methods into the reaction medium, e.g., a solution containing the halogen dissolved in an organic solvent can be introduced into the reaction mixture. A halogen-containing halogenated hydrocarbon solution, for example, chlorine in carbon tetrachloride is suitable for this purpose. The treatment with the halogen is suitably affected at low temperatures, preferably between 40 C. and room temperature, more advantageously between 30 C. and 0 C.

The compound of Formula X above can be converted into the compound of Formula III above via reaction step (11), by treating the compound of the Formula X with a dehydrohalogenating agent. The dehydrohalogenating agents which are utilized in this reaction are preferably proton acceptors such as for example, nitrogen-containing heterocyclic bases, e.g., pyridine, picoline or the like; or tri-lower alkyl amines, e.g., triethylamine; and alkali metal inorganic bases such as alkali hydroxide, e.g., sodium hydroxide or alkali bicarbonates, e.g., sodium bicarbonate. A suitable solvent for use in this reaction is the base itself. However, other solvents including the inert organic solvents, for example, ethers such as lower alkyl ethers, for example, ethyl ether or dioxane, chlorinated hydrocarbons, such as chloroform or carbon tetrachloride may also be employed. Dehydrohalogenation, carried out in accordance with reaction step (h), is suitably conducted between temperatures of from about 0 C. to C., although a temperature range of 0 to 50 C. is preferred. The preferred base for use in this dehydrohalogenation reaction is a nitrogen-containing heterocyclic base with pyridine being especially preferred.

In accordance with another embodiment of this invention, the compound of Formula IX can be directly converted to the compound of Formula III by carrying out the halogenation reaction of step (g) in the presence of the proton acceptor and a lower alkanoic acid such as propionic acid.

The same conditions utilized in the reaction of step (g) can be utilized to effect this direct conversion. In carrying out the conversion of compounds of the Formula IX to compounds of the Formula III either directly or Via the intermediate, i.e., compounds of the Formula X, at least one mole of the halogen is utilized per mole of the compound of Formula IX above. However, in accordance with this invention, it has been found that when a molar excess of the halogen which can be chlorine or bromine, i.e., at least 1.5 moles per mole of the compound of Formula IX above is utilized, the compound of Formula HI above is produced in higher yields and with greater purity. Therefore, in converting the compound of Formula IX to the compound of the Formula III either directly or via in intermediate (compound of the Formula X), it is preferred to utilize from 1.5 to 2 moles of the halogen per mole of the compound of Formula IX above. If desired, a larger excess than 2 moles of the halogen can be utilized. However, since no additional benefits result from utilizing large excesses of the halogen, amounts of halogen greater than 2 moles per mole of the compound of Formula IX are seldom utilized.

The compound of Formula III can be converted to the compound of Formula I, in accordance with this invention by the following reaction scheme:

wherein R R R R R and n are as above.

The compound of Formula III is converted to the compound of Formula XI via reaction step (i) by refluxing the compound of Formula III With an alkali metal iodide, preferably sodium iodide followed by the addition of lower alkanoic acid. Alternatively, the compound of Formula III can be converted to the compound of Formula XI by refluxing the compound of Formula III with an alkali metal iodide in the presence of a lower alkanoic acid preferably acetic acid. This reaction is generally carried out in the presence of an inert organic solvent. Among the preferred solvents are the ketone solvents such as acetone, methyl ethyl ketone, etc.

The compound of Formula XI is converted to the compound of Formula I by treating the compound of Formula XI with a lower alkanoic acid anhydride. Any of the conventional alkanolating conditions can be utilized in carrying out this reaction. This reaction is carried out in the presence of an acid catalyst. Any of the conventional acid catalysts such as those hereinbefore mentioned can be utilized. Generally, it is preferred to utilize para-toluene sulfonic acid as the acid catalyst. Generally, the lower alkanoic acid anhydride will serve as the solvent for the reaction medium. However, if desired, an inert organic solvent can be added to the reaction medium. Any conventional inert organic solvent will senve this purpose. The reaction can be carried out at room temperature. However, if desired, higher or lower temperatures can be utilized.

The following examples are illustrative of this invention but not limitative thereof. All temperatures in the examples are stated in degrees Centigrade.

EXAMPLE 1 Preparation of 16p-chloromethyl-5u,6p-dichloro-3flhydroxy-l6a,17a-epoxypregnan-20-one acetate To a cooled solution (0) of 50 g. (0.13 mole) of 33,1741 dihydroxy 1-6 methylenepregn 5 en-20-one 3-acetate in 1 liter of dry benzene containing 17 ml. of dry pyridine was added (over a 1 hour period) 264 ml. of a 1.08 molar solution (10% excess) of chlorine in carbon tetrachloride. The mixture was stirred at 0 for 30 minutes and the White precipitate was filtered and washed thoroughly with benzene. The benzene washings were combined and set aside. The precipitate (dried under reduced pressure) was stirred into 200 m1. of water and was again filtered to give 28 g. of crude product.

The original benzene solution was now washed with a 10% solution of sodium thiosulfate, 1 N hydrochloric acid (to remove excess pyridine), 5% sodium bicarbonate solution, and finally with a saturated solution of sodium chloride. The benzene solution was dried (MgSO and the solvent was removed under reduced pressure to give additional crude product. The two crops were combined, dissolved in methylene chloride and filtered from a small amount of insoluble material. The resulting solution was treated with charcoal, the residue obtained after removing the solvent under reduced pressure was crystallized from methylene chloride-methanol to give 16/3- chloromethyl 511,65 dichloro 3B hydroxy 16a,17aepoxypregnan 20 one. acetate. Concentration of the mother liquor gave an additional product.

EXAMPLE 2 Preparation of l6/3-chloromethyl-5a,6[3dichloro- 318-hydroxy-161x,17u-epoxypregnan-20-one To a suspension of 41 g. (0.0825 mole) of l6fl-ch1oromethyl-5a,6fi-dichloro-3fl-hydroxy 160:,17oz epoxypregnan-20-one acetate in 800 ml. of tetrahydrofuran was added 615 ml. of a 1% solution of potassium hydroxide in ethanol. The mixture was stirred at room temperature for 2 hours after which time most of the solvent was removed under reduced pressure. To the residue was added 500 ml. of ice water and the resulting precipitate tfiltered, washed with water, and dried for 2 hours under house vacuum. The product was dissolved in benzene, dried (MgSO and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give 16 3-chloromethyl-5a,6,8-dichloro-Bfi-hydroxy-16a,l7u-epoxypregnan-20-one.

EXAMPLE 3 Preparation of 16fi-chloromethyl-5u,6fl-dichloro- 16a,l7a-epoxypregnan-3,20-dione To a cooled (0) solution of 32 g. (0.0712 mole) of l6B-chloromethyl-5u,6 8-dichloro 3,3 hydroxy-16a,17aepoxypregnan-ZO-one in 320 m1. of acetone 1 was added (over a period of 15 minutes) 29.3 ml. (10% excess) of Jones reagent. The reaction mixture was stirred for an additional 10 minutes at 0 and most of the acetone was then removed under reduced pressure at 2530. Ice water (2 liters) was added to the residue and the precipitate was filtered and washed with 3 liters of Water. The product was dried for 2 hours under house vacuum to give 16,3 chloromethyl-5a,6fi-dichloro-l6a,17a-epoxypreguan- 3,20-dione.

The acetone was purified by refluxing with successive small portions of potassium permanganate until the violet color persisted. It was then distilled,

The oxidizing agent was prepared from 13.30 g. (lll'tllllllllll trioxnle and 11.5 ml. of concentrated sulfuric acid. The resultnlig mixture was diluted with water to a final volume of 9 EXAMPLE 4 Preparation of 618-chloro-16 S-chloromethyl- 16a,17ot-epoxypregn-4-ene-3,20-dione To a stirred suspension of 31 g. of sodium acetate in 1550 ml. of 95% ethanol was added 31 g. (0.0692 mole) of 1613 chloromethyl-5a,6fl-dichloro-l6a,l7u-epoxypregnan-3,20-dione and the mixture was refluxed for 1 hour. The solvent was then removed under reduced pressure and the residue was treated with 1 liter of ice water. The precipitate was filtered-and the residue was washed with 3 liters of water. The product was dried overnight (under house vacuum) and then triturated with diethyl ether to give 6B-chloro-16fl-chloromethyl-16u,17a-epoxypregn 4- ene-3,20-dione.

EXAMPLE 5 Preparation of 6,8-chloro-16B-chloromethyl-3-ethoxy- 16a,17ot-epoxypregna-3,1-dien-20-one To a solution of 22.6 g. of 6,8-chloro-16fi-chloromethyl- 16a,17a-epoxypregn-4-ene3,20-dione dissolved in 226 ml. of dry dioxane was added 22.6 ml. of redistilled triethyl orthoformate and 1.13 g. of sulfosalicylic acid monohydrate. The solution was then stirred for 5 hours at room temperature under nitrogen. At the end of this time, the solution was cooled to and 7.5 ml. of pyridine was added, followed by the dropwise addition (30 minutes) of 600 ml. of ice water. After stirring at room temperature for 2 hours, the precipitate was filtered, washed with water and dried overnight under house vacuum to give 6/8-chloro-l6fi-chlorornethyl-3-ethoxy 16a,17ot epoxypregna-3,5-dien-20-one.

EXAMPLE 6 Preparation of 165-chloromethyl-4,BB-dichloro- 1612,17 a-epoxypregna-4,6-diene-3,20-dione To a solution of 2 g. (0.0045 mole) of 6,8-chloro-16 3- chloromethyl-3-ethoxy 16a,17u epoxypregna-3,5-dien- 20-one in 100 ml. of glacial acetic acid and 9 ml. of water was added 9.8 g. of activated manganese dioxide. The mixture was stirred vigorously for 0.5 hour and was then filtered through a bed of diatomaceous silica. The solids were washed with methylene chloride and the filtrate was then evaporated under reduced pressure (bath temperature about 40). The residual acetic acid was removed under high vacuum at 40. The oily residue was treated with 250 ml. of ice water and the resulting precipitate was filtered and washed thoroughly with water. The solid was dried under house vacuum overnight to give 16,8-ch1oromethyl-6-chloro-16a,17a-epoxypregna 4,6 diene-3,20- dione. This crude product (2 g.) was treated with 10ml. of benzene and the resulting colloidal suspension was washed through 20 g. of neutral alumina (Grade 1) with 500 ml. of benzene. The solvent was removed under reduced pressure to give 16B-chloromethyl-Gfi-chloro-16a, 17a-epoxypregna-4,6-diene-3,20-dione as a colorless foam.

To a cooled (0) solution of 1.3 g. of 16fi-chloromethyl-fi-chloro 160:,170; epoxypregna-4,6-diene-3,20- dione in 10 ml. of chloroform was added 2.8 m1. of a 1.13 molar solution of chlorine in carbontetrachloride. The reaction mixture was stirred at 0 for 1 hour and the solvent was then removed under reduced pressure. The residue was treated with hexane (10 ml.) and the solvent was again removed under reduced pressure to give 165- chloromethyl 4a,6}3,7a trichloro-l6a,l7a-epoxypregn-5- ene-3,20-dione as a light yellow foam. The residue was treated with ml. of dry pyridine and stirred at room temperature for 2 hours. The pale yellow solution was poured into-100 ml. of diethyl ether and the ether solution was extracted several times with 1 N sulfuric acid solution to remove all of the pyridine. The ether solution was dried (MgSO and the solvent was removed under reduced pressure to give 1.2 g. of a light yellow foam. The crude product was dissolved in ml. of benzene and washed through 10 g. of neutral alumina (Grade 1) with 10 300 ml. of benzene. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether to give 16/3-chlor0methyl-4,6B-dichloro-16oz, 17a-epoxypregna-4,6-diene-3,20-dione.

EXAMPLE 7 Preparation of 4,6-dichloro-l7a-hydroxy-l6-methylenepregna-4,6-dien-3,20-dione acetate To a stirred suspension of 3 g. of sodium iodide in 20 ml. of acetone was added 300 mg. of 16B-chloromethyl- 4,6 dichloro-l6a,17a-epoxypregna-4,6 -diene-3,20-dione and the mixture was refluxed for 24 hours. iAt the end of this time, 0.5 ml. of glacial acetic acid was added and refluxing was continued for an additional 2 hours. To the cooled dark solution was added 15 ml. of 0.1 N sodium thiosulfate solution and the acetone was then removed under reduced pressure. Water was added to the residue and the precipitate was filtered and washed thoroughly with water. The product was dried for 2 hours under house vacuum and was then dissolved in a minimum amount of ether. The yellow ether solution was washed with 0.1 N sodium thiosulfate solution, dried (MgSO and evaporated to give 4,6 dichloro-17a-hydroxy-16- methylene-pregna 4,6-dien-3,20-dione, which was used directly for the next step.

A mixture of 200 mg. of crude 4,6-dichloro-17a-hydroxy-16-methylenepregna-4,6-dien-3,20-dione, 1 ml. of acetic anhydride and 25 mg. of p-toluene sulfonic acid mono-hydrate was allowed to stir at room temperature for 3 hours. Water (50 ml.) was then added and the mixture was stirred for 1 hour. The precipitate was filtered, washed with water, and dried for 2 hours under house vacuum. The product was then dissolved in a minimum of methylene chloride and dried (MgSO The solvent was removed under reduced pressure and the residue was crystallized from methanol to give 4,6-dichloro-17a-hydroxy-l6- methylenepregna-4,6-dien-3,20-dione acetate.

EXAMPLE 8 Preparation of 6-chloro-16;8-chloromethyl-16a,17(3- epoxypregna-4,6-diene-3,20-dione To a solution of 40.5 g. of 6-chloro-16,6-chloromethyl- 3-ethoxy-l6u,l7a-epoxypregna3,S-dien-20-one in 730 ml. of aqueous tetrahydrofuran (prepared by diluting 40 ml. of H 0 to 800 ml. with THE) was added 42.0 g. (2

equiv.) of 2,3-dichloro-5,6-dicyanobenzoquinone, and the mixture was allowed to remain at room temperature (ca. 20-24) for 2.25 hours. lDiethylether was added, and the organic phase was washed with 400 ml. of 1 N NaOH and three 400 ml. portions of saturated aqueous NaCl solution, dried (Na SO and concentrated to ca. 500 ml. in vacuo (50). The solution was then filtered over 610 g. of A1 0 and eluated with 2 liters of CH CI Removal of the solvent in vacuo (50) afforded 20.47 g. (54%) of 6 chloro 16 8-chloromethyl-16a,l7a-epoxypregna-4,6-diene-3,20-dione.

EXAMPLE 9 Preparation of 16fi-chloromethyl-4,6-dichloro-16a,l7u-

epoxypregna-4,6-diene-3 ,20-dione A solution of 20.47 g. of 6-chloro-16fl-chlorornethyl- 16a,17ot-epoxypregna-4,6-diene-3,20-dione in 200 ml. of CHCl was cooled in an ice-bath (to 0). To this was added 75.5 ml. (1.5 equiv.; 0.995 M) of C1 in CCL; and the solution was stirred at 0 for 0.5 hour. The solvent was removed in vacuo (50), and ml. of pyridine was added. The mixture was stirred at room temperature for 1 hour, and then diluted with 600 ml. of diethyl ether. The organic phase was washed with four 400 ml. portions of l N HCl, 400 ml. of 5% Na'HCO 400 ml. of saturated aqueous NaCl solution, dried (Na SO and the sol- Preparation: ea. 29 g. of C12 collected in 300 ml. of 0GB at room temperature. A 1 ml. aliquot in '10 ml. of 10% K1 solution and 1 m1. of HOAc was titrated with 0.1 N N ueSaOfl.

11 vent removed in vacuo (50). The crude product 1613- chloromethyl 4,6-dichloro-16a,17a-epoxypregna-4,6-diene-3,20-dione (24.15 g.) was dissolved in 60 ml. of benzene and filtered over 182 g. (ratio 1:75) of silica gel (0.005-0.2 mesh; 5 x 70 cm. column) to obtain:

Weight of Fraction Eluent product 1 2.5 liters benzene 9. 63 2 0.25 liter benzene 0. 87 3 0.25 liter benzene 0.78 4 5 liters CH C 11.16

wherein R and R are chlorine or bromine; and R is lower alkylidene; comprising refluxing a compound of the formula:

wherein R and R are as above; R is chlorine or bromine and n is an integer from to in an inert organic solvent medium with an alkali metal iodide in the presence of lower alkanoic acid or followed by the addition of a lower alkanoic acid.

2. The process of claim 1 wherein said alkali metal iodide is sodium iodide.

3. A process of producing a compound of the formula:

cun mup n wherein R and R are chlorine or bromine;

12 R is chlorine or bromine; and n is an integer from 0 to 5. comprising treating a compound of the formula:

CHRS (ca i it wherein R R R and n are as above; with a dehydrohalogenating agent.

4. The process of claim 3 wherein said dehydrohalogenating agent is pyridine.

5. The process of producing a compound of the formula:

wherein R R and R are chlorine or bromine; and n is an integer from 0 to 5; comprising treating a compound of the formula:

wherein R R and n are as above; with a halogen selected from the group consisting of chlorine or bromine in an inert organic solvent medium.

6. A process for producing a compound of the formula:

wherein R R and R are chlorine or bromine; and n is an integer from 0 to 5;

13 comprising treating a mono halo compound of the formula:

onnacm) .11

wherein R R and n are as above; with a halogen selected from the group consisting of chlorine or bromine in the presence of a proton acceptor or followed by the addition of a proton acceptor.

7. The process of claim 6 wherein the halogen is present in an amount of at least 1.5 moles per mole of the mono halo compound.

8. A process for producing a compound of the formula:

" CHRKCHz) H wherein R and R are chlorine or bromine; and n is an integer from 0 toS; comprising treating a 3-ether steroid of the formula:

12. A process for producing a compound of the formula:

"onmommr wherein R and R are chlorine or bromine; and n is an integer from 0 to 5;

comprising treating a compound of the formula:

a C=O wherein R R and n are as above; with a basic dehydrohalo'genating agent.

13. A process for producing a compound of the formula:

wherein R is a lower alkanoyl; R and R are chlorine or bromine; and n is an integer from 0 to 5; comprising reacting a 17 a-hydroxy steroid of the formula:

wherein R is as above; and

R is a lower alkylidene; with a halogen selected from the group consisting of chlorine or bromine in the presence of a nitrogen containing base, said halogen being present in an amount of at least 2 moles per mole of said l7a-steroid hydroxy compound.

14. The process of claim 13 wherein said nitrogen containing base is pyridine.

15. A compound of the formula:

wherein R R and R are chlorine or bromine; and

n is an integer from 0 to 5.

16. The compound of claim wherein said compound is 16,8 ch1oromethyl-4,6-dichloro-16a,17a-epoxypregna- 4,6-diene-3,20-dione.

17. A compound of the formula:

jionn wrmnri wherein R R and R are chlorine or bromine; and

n is an integer from 0 to 5.

18. The compound of claim 17 wherein said compound is 16,3 chloromethyl-4,6,7-trichloro-16a,17a-epoxypregn- 5-ene-3,20-dione.

19. A compound of the formula:

" CHR5(CH2) H wherein R and R are chlorine or bromine;

R is lower alkyl; and

n is an integer from 0 to 5.

24. The compound of claim 23 wherein said compound is 6-chloro 16p chloromethyl-3-ethoxy-16a,17a-epoxypregna-3,5-dien-20-one.

25. The compound 6,9 chloro-16/3-chloromethyl-16a, 17a-epoxypregn-4-ene-3,20-dione.

References Cited UNITED STATES PATENTS 3,296,075 1/1967 Kirk et a]. 167-74 3,493,588 3/1970 Herzog et al. 260-397.4 3,318,921 5/1967 Edwards et a1. 260397.3

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 260397.4 

